Design and Evaluation of a Folate-Targeted PEG-MMAE Conjugate with Enzyme-Activated Drug Release for Enhanced Tumor Selectivity and Antitumor Efficacy

Polymer-drug conjugates hold significant promise for drug delivery applications. Water-soluble polymers prolong circulation, enhance solubility, reduce immunogenicity, and promote tumor accumulation via an enhanced permeability and retention effect. We first present the design and evaluation of an enzyme-activatable folate-targeted polyethylene glycol-monomethyl auristatin E conjugate. The folate-targeted conjugate <b>4A-BFA-11</b> maintains affinity for the folate receptor while achieving tumor enrichment through the synergistic effects of PEG-mediated prolonged circulation and folate-driven targeting. Subsequently, the conjugate undergoes enzymatic cleavage at the tumor site to release the active payload, enabling precise therapy. <i>In vivo</i> studies demonstrated that <b>4A-BFA-11</b>, constructed using a folate-targeting strategy and a multiarm PEG carrier, effectively prolongs circulation time, improves tumor selectivity, and enhances antitumor efficacy. This strategy offers a novel approach for the efficient delivery of potent cytotoxic drugs through an enzyme-controlled activation mechanism, significantly broadening the therapeutic window while reducing systemic toxicity.